Snapshot of Science is a monthly digest of publication summaries, press releases and blog posts featuring researchers from Massachusetts General Hospital.

Welcome to the March 2018 edition of Snapshot of Science. Here's a quick look at some recent publications, press releases and stories about the Mass General research community.

In this issue we highlight:

  • 22 new studies published in high impact journals, along with 21 summaries submitted by the research teams
  • 12 new research-related press releases from the Mass General Public Affairs office
  • 13 posts from the Mass General Research Institute blog

Publications List

*Author-submitted summaries available when indicated

IDENTIFYING REGULATOR OF TUMOR GROWTH IN PEDIATRIC TUMORS
Vangl2/RhoA Signaling Pathway Regulates Stem Cell Self-Renewal Programs and Growth in Rhabdomyosarcoma
Hayes MN, McCarthy K, Jin A, Oliveira ML, Iyer S, Garcia SP, [et al.] Langenau DM
Published in Cell Stem Cell on March 1, 2018 | *Summary available


ANALYZING RATES OF FIREARM INJURIES DURING NRA ANNUAL CONVENTIONS
Reduction in Firearm Injuries during NRA Annual Conventions
Jena AB, Olenski AR
Published in New England Journal of Medicine on March 1, 2018 | *Summary available | See press release


TESTING TREATMENT FOR MITOCHONDRIAL DISEASE
Randomized Dose-Escalation Trial of Elamipretide in Adults with Primary Mitochondrial Myopathy
Karaa A, Haas R, Goldstein A, Vockley J, Weaver WD, Cohen BH
Published in Neurology on March 2, 2018 | *Summary available


INVESTIGATING NEUROCOGNITIVE EFFECTS OF PROTON RADIOTHERAPY
Left Hippocampal Dosimetry Correlates with Visual and Verbal Memory Outcomes in Survivors of Pediatric Brain Tumors
Zureick AH, Evans CL, Niemierko A, Grieco JA, Nichols AJ, Fullerton BC, [et al.] Pulsifer MB
Published in Cancer on March 2, 2018 | *Summary available


OVERCOMING RESISTANCE TO ALK DRUGS IN LUNG CANCER
SHP2 Inhibition Restores Sensitivity in ALK-Rearranged Non-Small-Cell Lung Cancer Resistant to ALK Inhibitors
Dardaei L, Wang HQ, Singh M, Fordjour P, Shaw KX, Yoda S, [et al.] Hata AN, Benes CH, Li F, Engelman JA
Published in Nature Medicine on March 5, 2018 | *Summary available


DEVELOPING A DECODER TO MAP WORD MEANING WITH BRAIN ACTIVITY
Toward a Universal Decoder of Linguistic Meaning from Brain Activation
Pereira F, Lou B, Pritchett B, Ritter S, Gershman SJ, Kanwisher N, Botvinick M, Fedorenko E
Published in Nature Communications on March 6, 2018 | *Summary available


ANALYZING ENZYMES IN THE LIVER
Spatiotemporal Compartmentalization of Hepatic NADH and NADPH Metabolism
Goodman RP, Calvo S, Mootha VK
Published in Journal of Biological Chemistry on March 7, 2018 | *Summary available


REASSESSING BREAST CANCER SCREENING GUIDELINES FOR WOMEN OF COLOR
Race/Ethnicity and Age Distribution of Breast Cancer Diagnosis in the United States
Stapleton SM, Oseni TO, Bababekov YJ, Hung YC, Chang DC
Published in JAMA Surgery on March 7, 2018 | *Summary available | See press release


IDENTIFYING A GENETIC CONTRIBUTOR TO AORTIC ANEURYSM
An HDAC9-MALAT1-BRG1 Complex Mediates Smooth Muscle Dysfunction in Thoracic Aortic Aneurysm
Lino Cardenas CL, Kessinger CW, Cheng Y, MacDonald C, MacGillivray T, Ghoshhajra B, [et al.] Lindsay ME
Published in Nature Communications on March 8, 2018


IDENTIFYING NEURAL CIRCUIT AND GENETIC "SWITCH" LINKED WITH MEMORY AND PTSD
Dentate Granule Cell Recruitment of Feedforward Inhibition Governs Engram Maintenance and Remote Memory Generalization
Guo N, Soden ME, Herber C, Kim MT, Besnard A, Lin P, [et al.] Sahay A
Published in Nature Medicine on March 12, 2018 | *Summary available | See press release


TESTING FEASIBILITY OF INTERVENTION FOR SURVIVORS OF HEMATOPOIETIC STEM CELL TRANSPLANT
Pilot Study of a Multimodal Intervention to Enhance Sexual Function in Survivors of Hematopoietic Stem Cell Transplantation
El-Jawahri A, Fishman SR, Vanderklish J, Dizon DS, Pensak N, Traeger L, [et al.] Temel JS
Published in Cancer on March 14, 2018 | *Summary available


LINK BETWEEN OBESITY AND RESISTANCE TO ANTIANGIOGENIC THERAPY FOR BREAST CANCER
Obesity Promotes Resistance to Anti-VEGF Therapy in Breast Cancer by Up-Regulating IL-6 and Potentially FGF-2
Incio J, Ligibel JA, McManus DT, Suboj P, Jung K, Kawaguchi K, [et al.] Fukumura D, Jain RK
Published in Science Translational Medicine on March 14, 2018 | *Summary available | See press release


NEW METHOD FOR DIAGNOSING SEPSIS
Diagnosis of Sepsis From a Drop of Blood by Measurement of Spontaneous Neutrophil Motility in a Microfluidic Assay
Ellett F, Jorgensen J, Marand AL, Liu YM, Martinez MM, Sein V, [et al.] Irimia D
Published in Nature Biomedical Engineering on March 19, 2018 | *Summary available | See press release


GENETIC MUTATION CAUSING PRENTAL DEATH
An Inactivating Mutation in the Histone Deacetylase SIRT6 Causes Human Perinatal Lethality
Ferrer CM, Alders M, Postma AV, Park S, Klein MA, Cetinbas M, [et al.] Mostoslavsky R
Published in Genes & Development on March 19, 2018 | *Summary available


COMPARING TREATMENTS FOR POSTMENOPAUSAL VAGINAL DISCOMFORT
Efficacy of Vaginal Estradiol or Vaginal Moisturizer vs Placebo for Treating Postmenopausal Vulvovaginal Symptoms
Mitchell CM, Reed SD, Diem S, Larson JC, Newton KM, Ensrud KE, [et al.] Guthrie KA
Published in JAMA Internal Medicine on March 19, 2018 | *Summary available | See press release


AI TECHNIQUE IMPROVES QUALITY OF MEDICAL IMAGING
Image Reconstruction by Domain-Transform Manifold Learning
Zhu B, Liu JZ, Cauley SF, Rosen BR, Rosen MS
Published in Nature on March 21, 2018 | *Summary available | See press release


NEW INSIGHT INTO LYMPH NODE METASTASES
Lymph Node Metastases Can Invade Local Blood Vessels, Exit the Node, and Colonize Distant Organs in Mice
Pereira ER, Kedrin D, Seano G, Gautier O, Meijer EFJ, Jones D, [et al.] Padera TP
Published in Science on March 23, 2018 | *Summary available | See press release


UNDERSTANDING FUNCTION OF IMMUNOTHERAPY DRUG IPILIMUMAB
Anti–CTLA-4 Therapy Requires an Fc Domain for Efficacy
Ingram JR, Blomberg OS, Rashidian M, Ali L, Garforth S, Fedorov E, [et al.] Ploegh HL, Dougan M
Published in PNAS on March 26, 2018 | *Summary available


A FRAMEWORK FOR CONSIDERING TUMOR PLASTICITY THROUGH THE LENS OF NORMAL DEVELOPMENT
Developmental History Provides a Roadmap for the Emergence of Tumor Plasticity
Tata PR, Chow RD, Saladi SV, Tata A, Konkimalla A, Bara A, [et al.] Rajagopal J
Published in Developmental Cell on March 26, 2018 | *Summary available


ASSESSING HOSPITAL READMISSION RATES
Applicability of Publicly Reported Hospital Readmission Measures to Unreported Conditions and Other Patient Populations: A Cross-Sectional All-Payer Study
Butala NM, Kramer DB, Shen C, Strom JB, Kennedy KF, Wang Y, Valsdottir LR, Wasfy JH, Yeh RW
Published in Annals of Internal Medicine on March 27, 2018 | *Summary available


INVESTIGATING E-CIGARETTES' USEFULNESS FOR QUITTING SMOKING
Association of E-Cigarette Use With Smoking Cessation Among Smokers Who Plan to Quit After a Hospitalization: A Prospective Study
Rigotti NA, Chang Y, Tindle HA, Kalkhoran SM, Levy DE, Regan S [et al.] Singer DE
Published in Annals of Internal Medicine on March 27, 2018 | *Summary available | See press release


ASSESSING HEALTH CARE ACCESS AND AFFORDABILITY FOR CANCER SURVIVORS
Patterns in Health Care Access and Affordability Among Cancer Survivors During Implementation of the Affordable Care Act
Nipp RD, Shui AM, Perez GK, Kirchhoff AC, Peppercorn JM, Moy B, Kuhlthau K, Park ER
Published in JAMA Oncology on March 29, 2018 | *Summary available


Publication Summaries

1. IDENTIFYING REGULATOR OF TUMOR GROWTH IN PEDIATRIC TUMOR
Vangl2/RhoA Signaling Pathway Regulates Stem Cell Self-Renewal Programs and Growth in Rhabdomyosarcoma
Hayes MN, McCarthy K, Jin A, Oliveira ML, Iyer S, Garcia SP, [et al.] Langenau DM
Published in Cell Stem Cell on March 1, 2018

Tumor growth and relapse are driven by rare cell types that display similarities to normal tissue stem cells. Yet, identification of these cells and key pathways that drive their survival has been elusive. This is especially true for rhabdomyosarcoma – a pediatric tumor of the muscle. Our recent work has identified Van Gogh-like 2 (Vangl2) as a novel marker of tumor stem cells in rhabdomyosarcoma. Our work also shows that VANGL2 directly regulates tumor growth and the survival of rare relapse driving cell types. This work is important because it now allows for identification of human cells that sustain tumor growth and provides novel therapeutic targets for treatment of this disease.

(Summary submitted by David Langenau, PhD, of the Department of Pathology, the Cancer Center and Center for Regenerative Medicine)


2. ANALYZING RATES OF FIREARM INJURIES DURING NRA ANNUAL CONVENTIONS
Reduction in Firearm Injuries during NRA Annual Conventions
Jena AB, Olenski AR
Published in New England Journal of Medicine on March 1, 2018

This study analyzed rates of firearm injuries during dates of National Rifle Association annual conventions compared to injury rates during identical days in the surrounding weeks. Using a large insurance database, we hypothesized that firearm injury rates would fall during convention dates due to a brief period of reduced firearm use, due either to convention attendance itself or the closure of venues where firearms are used. We found a 20% reduction in firearm injury rates during NRA convention dates, which is consistent with the hypothesis that firearm injuries may be reduced even among presumably trained and experienced users when firearms aren’t used.

(Summary submitted by Anupam Jena, MD, of the Department of Medicine)


3. TESTING TREATMENT FOR MITOCHONDRIAL DISEASE
Randomized Dose-Escalation Trial of Elamipretide in Adults with Primary Mitochondrial Myopathy
Karaa A, Haas R, Goldstein A, Vockley J, Weaver WD, Cohen BH
Published in Neurology on March 2, 2018

Mitochondrial disease is a group of rare and disabling disorders which, in adults, primarily affect muscles. This study looked at the safety, tolerability, and efficacy of elamipretide; an experimental drug for the treatment of these adult patients. For this clinical trial, 36 participants with genetically confirmed mitochondrial disease received intravenous elamipretide (0.01, 0.1, and 0.25 mg/kg/h or placebo). After 5 days of treatment participants who received the highest dose of elamipretide were able to walk a longer distance compared to participants who received placebo without increased safety concerns. These findings are encouraging and merit further studies to see the effect of longer treatment periods for individuals affected by this condition.

(Summary submitted by Amel Karaa, MD, of the Department of Pediatrics)


4. INVESTIGATING NEUROCOGNITIVE EFFECTS OF PROTON RADIOTHERAPY
Left Hippocampal Dosimetry Correlates with Visual and Verbal Memory Outcomes in Survivors of Pediatric Brain Tumors
Zureick AH, Evans CL, Niemierko A, Grieco JA, Nichols AJ, Fullerton BC, [et al.] Pulsifer MB
Published in Cancer on March 2, 2018

Children treated with radiotherapy for brain tumors experience late neurocognitive deficits that can impact academic success. Proton radiotherapy (PRT) may reduce late effects because it spares healthy tissue outside the target region. In the first report to date, we examined memory and radiation dose to the hippocampus in children treated with PRT. Memory scores were normal and effectively stable at follow-up, indicating promising outcome for PRT patients. Higher dose to the left hippocampus was associated with verbal memory decline, particularly for female patients. Radiation planning should minimize left hippocampus dose to preserve verbal memory in pediatric survivors treated with PRT.

(Summary submitted by Margaret B. Pulsifer, PhD and Julie A. Grieco, PsyD, of the Department of Psychiatry)


5. OVERCOMING RESISTANCE TO ALK DRUGS IN LUNG CANCER
SHP2 Inhibition Restores Sensitivity in ALK-Rearranged Non-Small-Cell Lung Cancer Resistant to ALK Inhibitors
Dardaei L, Wang HQ, Singh M, Fordjour P, Shaw KX, Yoda S, [et al.] Hata AN, Benes CH, Li F, Engelman JA
Published in Nature Medicine on March 5, 2018

Drugs that target the protein ALK have shown superior efficacy and better tolerability than traditional chemotherapeutics in lung cancer patients whose tumors are driven by ALK activation. Unfortunately, these responses are transient, and acquired drug resistance invariably develops. Many different mechanisms of resistance to ALK targeting have been identified, posing challenges for selection of the most appropriate subsequent treatment. We discovered that a novel drug against the protein SHP2 was able to broadly restore sensitivity to ALK drugs in resistant tumor models. This suggests a unified therapeutic strategy for overcoming acquired resistance to ALK drugs in lung cancer.

(Summary submitted by Cyril Benes, PhD, and Aaron Hata, MD, PhD, of the Cancer Center)


6. DEVELOPING A DECODER TO MAP WORD MEANING WITH BRAIN ACTIVITY
Toward a Universal Decoder of Linguistic Meaning from Brain Activation
Pereira F, Lou B, Pritchett B, Ritter S, Gershman SJ, Kanwisher N, Botvinick M, Fedorenko E
Published in Nature Communications on March 6, 2018

Humans are the only species who can translate abstract thoughts into a share-able code: language. What is the nature of our knowledge representations and how do we implement the mapping between thoughts and language? Using distributional models of word meanings where each word is defined by other words it co-occurs with, we trained a decoder on the mapping between different meaning dimensions and brain activation patterns. This decoder could then successfully distinguish between the meanings of new diverse sentences, even in cases where sentences talk about similar topics. These results suggest that the model we have built is broad-coverage and yet fine-grained enough to represent a rich array of linguistic meanings.

(Summary submitted by Evelina Fedorenko, PhD, of the Department of Psychiatry)


7. ANALYZING ENZYMES IN THE LIVER
Spatiotemporal Compartmentalization of Hepatic NADH and NADPH Metabolism
Goodman RP, Calvo S, Mootha VK
Published in Journal of Biological Chemistry on March 7, 2018

NAD+ and NADP+ are small molecules found in all living cells that are used by hundreds of different enzymes in the reduction and oxidation (redox) reactions that drive cellular metabolism. They are particularly important in the liver, which is a central hub of organismal metabolism. Our paper uses a bioinformatic approach to define the NADPome, i.e. all enzymes that use, consume, or produce NAD or NADP, in the liver. It demonstrates important aspects of how NAD+ and NADP+ utilizing enzymes are distributed within cells, which has important implications for disease linked to NAD+ and NADP+ metabolism, such as diabetes and fatty liver disease.

(Summary submitted by Russell Goodman, MD, Dphil, of the Department of Medicine and Gastroenterology)


8. REASSESSING BREAST CANCER SCREENING GUIDELINES FOR WOMEN OF COLOR
Race/Ethnicity and Age Distribution of Breast Cancer Diagnosis in the United States
Stapleton SM, Oseni TO, Bababekov YJ, Hung YC, Chang DC
Published in JAMA Surgery on March 7, 2018

Current guidelines recommend beginning mammograms at age 50. Our study found that these guidelines that were developed based on the majority population may not be applicable to minority women. More specifically, we found that nonwhite women tended to get breast cancer in their 40s – a full two decades earlier than whites, and too soon to benefit from mammograms begun at age 50. These results suggest that flawed science may contribute to healthcare disparities more so than flawed care. It’s important to respect racial differences at the scientific research stage in order to improve delivery of clinical care. Physicians and physician scientists must also be made aware of these hidden biases.

(Summary submitted by David Chang, PhD, of the Department of Surgery)


9. IDENTIFYING NEURAL CIRCUIT AND GENETIC 'SWITCH' LINKED WITH MEMORY AND PTSD
Dentate Granule Cell Recruitment of Feedforward Inhibition Governs Engram Maintenance and Remote Memory Generalization
Guo N, Soden ME, Herber C, Kim MT, Besnard A, Lin P, [et al.] Sahay A
Published in Nature Medicine on March 12, 2018

Memories become less precise and generalized over time as memory traces reorganize within the brain’s networks. This phenomenon is thought to underlie overgeneralization of fear in post-traumatic stress disorder (PTSD) and memory imprecision in aging. In this study, we identify a neural circuit mechanism involved in preserving the specificity of memories. We also identify a genetic “switch” that can slow down memory generalization. These findings have implications for improving memory in aging individuals and reducing symptoms of PTSD.

(Summary submitted by Amar Sahay, PhD, of the Department of Psychiatry and Center for Regenerative Medicine)


10. TESTING FEASIBILITY OF INTERVENTION FOR SURVIVORS OF HEMATOPOIETIC STEM CELL TRANSPLANT
Pilot Study of a Multimodal Intervention to Enhance Sexual Function in Survivors of Hematopoietic Stem Cell Transplantation
El-Jawahri A, Fishman SR, Vanderklish J, Dizon DS, Pensak N, Traeger L, [et al.] Temel JS
Published in Cancer on March 14, 2018

Sexual dysfunction is one of the most common complications affecting allogeneic hematopoietic stem cell transplant survivors. Yet, interventions to enhance sexual function in this population are lacking. Our team recently conducted a pilot study using a pre-/post study design to assess the feasibility and potential benefit of a multimodal intervention to address sexual dysfunction in stem cell transplant survivors. We demonstrated that the intervention was feasible and led to statistically and clinically significant improvement in patients’ satisfaction and interest in sex, sexual health and function including orgasm, erectile function, lubrication, and vaginal comfort. Patients also reported clinically significant improvement in their quality of life, and depression and anxiety symptoms.

(Summary submitted by Areej El-Jawahri, MD, of the Cancer Center)


11. LINK BETWEEN OBESITY AND RESISTANCE TO ANTIANGIOGENIC THERAPY FOR BREAST CANCER
Obesity Promotes Resistance to Anti-VEGF Therapy in Breast Cancer by Up-Regulating IL-6 and Potentially FGF-2
Incio J, Ligibel JA, McManus DT, Suboj P, Jung K, Kawaguchi K, [et al.] Fukumura D, Jain RK
Published in Science Translational Medicine on March 14, 2018

Obesity is known to fuel tumor progression and confer treatment resistance, but the underlining mechanisms are poorly understood. In this study, we report for the first time that obesity and intratumor adipocyte-associated molecules – adipokines – confer resistance to antiangiogenic therapy in breast cancer. The approval of anti-angiogenic therapy for breast cancer was revoked by FDA due to lack of improvement in survival. With nearly 70 percent of breast cancer patients being overweight or obese upon diagnosis, this study uncovers underlying mechanisms and suggests strategies for improved outcomes in these patients.

(Summary submitted by Rakesh Jain, PhD, Dai Fukumura, MD, PhD, and João Incio, MD, PhD, of the Department of Radiation Oncology)


12. NEW METHOD FOR DIAGNOSING SEPSIS
Diagnosis of Sepsis From a Drop of Blood by Measurement of Spontaneous Neutrophil Motility in a Microfluidic Assay
Ellett F, Jorgensen J, Marand AL, Liu YM, Martinez MM, Sein V, [et al.] Irimia D
Published in Nature Biomedical Engineering on March 19, 2018

From Jack Daniel to Mohammed Ali to Superman (Christopher Reeve), the deadly syndrome sepsis (a.k.a. “blood-poisoning”) shows little discrimination in who it targets. The condition is often misdiagnosed, delaying treatment. Recently, in a collaborative work that included researchers and surgeons at MGH, we have developed a new method for diagnosing sepsis with higher accuracy. The method relies on the analysis of one drop of blood and the atypical movement of one type of white blood cell, neutrophils, through microscopic mazes. This promising new approach may provide doctors with better tools for sepsis detection and could create new opportunities for more effective treatment.

(Summary submitted by Daniel Irimia, PhD, MD, of the Department of Surgery)


13. GENETIC MUTATION CAUSING PRENTAL DEATH
An Inactivating Mutation in the Histone Deacetylase SIRT6 Causes Human Perinatal Lethality
Ferrer CM, Alders M, Postma AV, Park S, Klein MA, Cetinbas M, [et al.] Mostoslavsky R
Published in Genes & Development on March 19, 2018

In many cases, prenatal death cannot be attributed to chromosomal irregularities, suggesting that in those cases, specific genetic defects may depend on single-nucleotide mutations in developmentally-important genes. Using whole-Exome Sequencing, we identified the first such case of a mutation in a gene coding for SIRT6, an enzyme regulating compaction of DNA in a structure called chromatin. Chromatin compaction is a key event in modulating activation and silencing of genes. In our study, we identified a family with four siblings that died perinatally, all of them carrying a homozygous mutation in SIRT6. We found that the mutation completely inactivated SIRT6, causing de-repression of important early developmental genes, in turn driving major neural and heart developmental defects. With the advent of DNA sequencing technologies in the clinic, it will be plausible to determine whether this mutation may be an important contributor to perinatal death.

(Summary submitted by Raul Mostoslavsky, MD, PhD, of the Cancer Center and Center for Regenerative Medicine)


14. COMPARING TREATMENTS FOR POSTMENOPAUSAL VAGINAL DISCOMFORT
Efficacy of Vaginal Estradiol or Vaginal Moisturizer vs Placebo for Treating Postmenopausal Vulvovaginal Symptoms
Mitchell CM, Reed SD, Diem S, Larson JC, Newton KM, Ensrud KE, [et al.] Guthrie KA
Published in JAMA Internal Medicine on March 19, 2018

Close to half of postmenopausal women have symptoms of vaginal pain, irritation or dryness with sex. We evaluated two common treatments for postmenopausal vaginal discomfort: 302 women were randomized to a prescription vaginal estradiol tablets + placebo gel, an over the counter moisturizer + placebo tablet or dual placebo. Women in all three arms of the trial had a similar decrease in most bothersome symptom severity after 12 weeks of treatment. Over half of women in each arm had a greater than 50% decrease in symptom severity, however the lack of complete improvement in any of the arms suggests that better treatments for this condition are necessary.

(Summary submitted by Caroline Mitchell, MD, of the Department of Obstetrics & Gynecology)


15. AI TECHNIQUE IMPROVES QUALITY OF MEDICAL IMAGING
Image Reconstruction by Domain-Transform Manifold Learning
Zhu B, Liu JZ, Cauley SF, Rosen BR, Rosen MS
Published in Nature on March 21, 2018

In the same way that humans learn how to see through real-world experience, we have trained medical imaging systems to see with deep learning. Our A.I. technology (called AUTOMAP) allows imaging systems to automatically learn how to properly image a subject in a wide variety of scenarios, with improved accuracy and speed. Ultimately for the patient, this means significantly reduced scan times and cost. In the future, our innovation will enable development of smaller and more portable imaging systems. Although our research primarily demonstrated this on medical imaging systems (MRI/CT/PET), it can be readily applied to other forms of imaging (e.g. optical, RADAR, LIDAR) for applications ranging from radio astronomy to industrial sensing applications.

(Summary submitted by Matthew Rosen, PhD, of the Martinos Center for Biomedical Imaging)


16. NEW INSIGHT INTO LYMPH NODE METASTASES
Lymph Node Metastases Can Invade Local Blood Vessels, Exit the Node, and Colonize Distant Organs in Mice
Pereira ER, Kedrin D, Seano G, Gautier O, Meijer EFJ, Jones D, [et al.] Padera TP
Published in Science on March 23, 2018

The first place cancer cells spread is often the lymph node that drains the site of the primary tumor. Whether these cancer cells that arrive in the lymph can spread further to organs such as the lung, liver, bone and brain—sites where the spread of cancer is often fatal—has been controversial. In this study, we directly show that metastatic cancer cells in mice can escape the lymph node by invading lymph node blood vessels to become a source of tumors that grow in distant organs.

(Summary submitted by Timothy Padera, PhD, of the Department of Radiation Oncology)


17. UNDERSTANDING FUNCTION OF IMMUNOTHERAPY DRUG IPILIMUMAB
Anti–CTLA-4 Therapy Requires an Fc Domain for Efficacy
Ingram JR, Blomberg OS, Rashidian M, Ali L, Garforth S, Fedorov E, [et al.] Ploegh HL, Dougan M
Published in PNAS on March 26, 2018

Ipilimumab is the first in a class of drugs that uses the immune system to treat cancer. Ipilimumab binds to a protein on T cells called CTLA-4, but it is unclear how ipilimumab works. We developed an alpaca antibody fragment that binds tightly to CTLA-4 and blocks its activity, but lacks a portion of the antibody called the Fc domain that communicates with other immune cells. This fragment could not cause tumor regression without the Fc. This finding implies that blocking CTLA-4 is insufficient to cause tumor regression, and that communicating with other immune cells through the Fc is critical.

(Summary submitted by Michael Dougan, MD, PhD, of the Department of Gastroenterology)



18. A FRAMEWORK FOR CONSIDERING TUMOR PLASTICITY THROUGH THE LENS OF NORMAL DEVELOPMENT
Developmental History Provides a Roadmap for the Emergence of Tumor Plasticity
Tata PR, Chow RD, Saladi SV, Tata A, Konkimalla A, Bara A, [et al.] Rajagopal J
Published in Developmental Cell on March 26, 2018

Our study shows that cancer cells of one organ can become more like cells from another organ and we call this behavior “cell plasticity”. Regulatory proteins that control what identity a cell has (like liver, lung, or intestine) are often mutated in cancer. We showed that when you manipulate these proteins, a lung cancer can stop expressing lung genes and instead express the genes of other organs including the intestine and esophagus. Indeed, the cancer cells adopt the “fate” of cells that were closest to them in the developing embryo. Cancers may use this form of “identity theft” to become resistant to chemotherapy. Targeting this plasticity may be another way to treat cancers.

(Summary submitted by Jayaraj Rajagopal, MD, of the Department of Medicine)


19. ASSESSING HOSPITAL READMISSION RATES
Applicability of Publicly Reported Hospital Readmission Measures to Unreported Conditions and Other Patient Populations: A Cross-Sectional All-Payer Study
Butala NM, Kramer DB, Shen C, Strom JB, Kennedy KF, Wang Y, Valsdottir LR, Wasfy JH, Yeh RW
Published in Annals of Internal Medicine on March 27, 2018

In this study, we examined whether the main publicly-reported readmissions measures used by Medicare to penalize hospitals are applicable to non-penalized conditions and non-Medicare populations. We found wide variation in hospital performance on readmissions for these different groups of patients. We also found that half of hospitals would have a change in penalty status if it were based on the Medicare non-penalized or the non-Medicare groups of patients. This suggests that what is currently being publicly reported and penalized is not the whole picture. The development of more complete all-payer databases would shine more light on hospital performance on readmissions for all patients.

(Summary submitted by Neel Butala, MD, of the Department of Medicine)


20. INVESTIGATING E-CIGARETTES' USEFULNESS FOR QUITTING SMOKING
Association of E-Cigarette Use With Smoking Cessation Among Smokers Who Plan to Quit After a Hospitalization: A Prospective Study
Rigotti NA, Chang Y, Tindle HA, Kalkhoran SM, Levy DE, Regan S [et al.] Singer DE
Published in Annals of Internal Medicine on March 27, 2018

Few studies have evaluated the effectiveness of e-cigarettes for smoking cessation. Our study analyzed data from a clinical trial that enrolled hospitalized smokers who planned to quit after discharge. Participants were asked if they had used an e-cigarette in the 3 months after hospital discharge. Those who had used an e-cigarette were less likely to have quit smoking at 6 months. However, participants using e-cigarettes did so only intermittently and chose on their own whether or not to use e-cigarettes. E-cigarette users might have been individuals who were having more difficulty quitting, independent of their e-cigarette use. These results indicate the urgent need for randomized, controlled trials to investigate whether e-cigarettes can help smokers to quit.

(Summary submitted by Nancy Rigotti, MD, of the Department of Medicine)


21. ASSESSING HEALTH CARE ACCESS AND AFFORDABILITY FOR CANCER SURVIVORS
Patterns in Health Care Access and Affordability Among Cancer Survivors During Implementation of the Affordable Care Act
Nipp RD, Shui AM, Perez GK, Kirchhoff AC, Peppercorn JM, Moy B, Kuhlthau K, Park ER
Published in JAMA Oncology on March 29, 2018

Health care costs have increased in recent years, and thus we sought to conduct an updated analysis of cancer survivors’ ability to access and afford health care. We found that cancer survivors are more likely to experience problems accessing and affording needed health care compared with adults without a cancer history, despite being more likely to have health insurance and paid sick leave at work. Importantly, our findings suggest that survivors’ struggles to access and afford medical care decreased during our observation period, coincident with implementation of the Affordable Care Act (ACA), although we cannot attribute this to any specific ACA provision. Collectively, our results provide important evidence regarding the financial consequences of cancer.

(Summary submitted by Ryan Nipp, MD, MPH, of the Department of Medicine)

Press Releases

How Does Resolving Cannabis Problems Differ from Resolving Problems with Alcohol or Other Drugs?
Featuring John Kelly, PhD

Individuals who report having resolved a problem with cannabis use appear to have done so at younger ages and with less assistance than those who resolved problems with alcohol or other drugs, report investigators from the Recovery Research Institute at Massachusetts General Hospital.


Breast Cancer Screening Guidelines May Lead to Delayed Diagnosis in Nonwhite Women
Featuring David Chang, PhD, MBA, MPH

The current guidelines for mammographic breast cancer screening, which are based on data from primarily white populations, may lead to delayed diagnosis in nonwhite women, according to a report from Massachusetts General Hospital investigators.


Mass. General Investigators Identify Neural Circuit, Genetic 'Switch' that Maintain Memory Precision
Featuring Amar Sahay, PhD

Investigators from Massachusetts General Hospital and the Harvard Stem Cell Institute have identified a neural circuit involved in preserving the specificity of memories and a genetic 'switch' that can slow down memory generalization – the loss of specific details that occurs in both age-related memory impairment and in PTSD.


Obesity May Promote Resistance to Antiangiogenic Therapy for Breast Cancer
Featuring Joao Incio, MD, PhD, and Dai Fukumura, MD, PhD

A research team led by Massachusetts General Hospital has found, for the first time, that obesity and obesity-related molecular factors appear to induce resistance to antiangiogenic therapy in breast cancer patients and in mouse models of the disease.


Measuring Neutrophil Motility Could Lead to Accurate Sepsis Diagnosis
Featuring Felix Ellett, PhD, Daniel Irimia, MD, PhD, and Jarone Lee, MD

A microfluidic device developed by Massachusetts General Hospital investigators may help solve a significant and persistent challenge in medicine – diagnosing the life-threatening complication of sepsis.


Vaginal Estrogen Tablets, Moisturizers and Placebo Gel All Can Improve Vaginal Discomfort
Featuring Caroline Mitchell, MD

A clinical trial comparing two treatments for postmenopausal vaginal discomfort – low-dose vaginal estrogen and a vaginal moisturizer – to placebo treatments found that both produced symptom improvements similar to those associated with the placebos after 12 weeks of treatment.


Learning to See: New Artificial Intelligence Technique Dramatically Improves the Quality of Medical Imaging
Featuring Bo Zhu, PhD, and Matt Rosen, PhD

Researchers with the Martinos Center for Biomedical Imaging at Massachusetts General Hospital have developed a new technique based on artificial intelligence and machine learning that should enable clinicians to acquire high-quality images from limited data.


Study Supports Biomarker Assay for Emergency Department Diagnosis of Acute Heart Failure
Featuring James Januzzi Jr., MD

A multi-institutional study led by a Massachusetts General Hospital physician supports the value of a biomarker to accurately diagnose or rule out acute heart failure in patients seen for shortness of breath at hospital emergency departments.


Metastatic Lymph Nodes Can Be the Source of Distant Metastases in Mouse Models of Cancer
Featuring Timothy Padera, PhD

A study by Massachusetts General Hospital investigators finds that, in mouse models, cancer cells from metastatic lymph nodes can escape into the circulation by invading nodal blood vessels, leading to the development of metastases in other parts of the body.


Metabolic Profiling May Determine Aggressiveness, Prognosis of Prostate Cancer
Featuring Leo L. Cheng, PhD

A new approach to analyzing prostate gland tissue developed by Massachusetts General Hospital researchers may help address a major challenge in treating prostate cancer – determining which tumors are unlikely to progress and which could be life threatening and require treatment.


Machine Learning Model Provides Rapid Prediction of C. Difficile Infection Risk
Featuring Erica Shenoy, MD, PhD

Investigators from Massachusetts General Hospital, the University of Michigan and Massachusetts Institute of Technology have developed investigational "machine learning" models that can predict a patient’s risk of developing C. difficile much earlier than it would be diagnosed with current methods.


Study Suggests Uncertainty in E-cigarettes' Usefulness for Quitting Smoking
Featuring Nancy Rigotti, MD

An analysis of data from a previous study of more than 1,350 smokers intending to quit after a hospitalization found that those who reported using electronic cigarettes during the study period were less likely to have successfully quit smoking 6 months after entering the study.


Blog Posts

Martinos Center Researcher Receives Award to Explore Anesthesia and Sleep
Featuring Laura Lewis, PhD

Martinos Center for Biomedical Imaging investigator Laura Lewis recently won the Society for Neuroscience Peter and Patricia Gruber International Research Award. Learn more Dr. Lewis and her research investigating what happens in the brain during sleep and anesthesia.


Pediatrician Engages Communities to Make a Lasting Impact on Child Health
Featuring Elsie Taveras, MD, MPH

Elsie Taveras, Chief of General Academic Pediatrics at MassGeneral Hospital for Children, is using clinical and community-based research approaches to address the causes of childhood health problems and reduce health disparities.


Macrophages Found to be the Source of a Ripple Effect in the Development of a Life-Threatening Heart Condition
Featuring Matthias Nahrendorf, MD, PhD, and Maarten Hulsmans, PhD

Like a pebble thrown into a still body of water, a new study from the Mass General Center for Systems Biology has found that white blood cells called macrophages create a ripple effect in the heart that can lead to development of a condition known as heart failure with preserved ejection fraction, or HFpEF. These findings provide new insight into how to prevent development of this life-threatening disease.


Could the Secret to a Good Night’s Sleep Be Found in Our Genes?
Featuring Jacqueline Lane, PhD

Could the secret to a good night's sleep be found in our genes? Research from Massachusetts General Hospital's Jacqueline Lane is uncovering why it takes more than counting sheep to get enough sleep.


Science Fair Inspires
Featuring Jamie Heather, PhD, Katia Canenguez, PhD, and Rick Schrenker

Massachusetts General Hospital's long-standing partnership with Timilty Middle School in Roxbury is helping to inspire the next generation of scientists. This year, more than 60 MGHers volunteered to judge the school's annual science fair, and 13 Timilty students participating in the MGH mentoring program have been selected to present their projects at the Boston citywide fair.


Celebrating Women in Science and Medicine: Interview with Erica Shenoy
Featuring Erica Shenoy, MD, PhD

Erica Shenoy, a physician-investigator in the Division of Infectious Diseases in the Department of Medicine at Mass General, talks about balancing the dual demands of career and family.


Postdoc Profile: Nabi M. Nurunnabi, PhD
Featuring Nabi M. Nurunnabi, PhD

Meet a Mass General postdoc: Md "Nabi" Nurunnabi from the Center for Systems Biology and the Cardiovascular Research Center is working on the design of nanoparticle-based treatments for diseases such as cancer, diabetes, fibrosis and cardiovascular diseases.


Celebrating Women in Science and Medicine: Interview with Daphne Holt
Featuring Daphne Holt, MD, PhD

Daphne Holt, a researcher in the Martinos Center for Biomedical Imaging and the Department of Psychiatry, talks about her career and how to encourage more women in science.


Mass General Researcher Receives Fellowship for Developing Color-Changing Bandage
Featuring Haley Marks, PhD

Haley Marks is a postdoctoral research fellow in the Mass General Wellman Center for Photomedicine. She recently received a fellowship for her research on the development of a color-changing bandage that monitors the skin’s response to injury.


Multiple Sclerosis Treatments are Advancing, But There is Still More Work To Be Done
Featuring Farrah Mateen, MD, PhD

In recognition of National MS Awareness Month, Farrah Mateen of the Multiple Sclerosis Clinic at Mass General discusses treatment options for MS patients and how research could help in diagnosing and monitoring the disease.


Celebrating Women in Science and Medicine: Interview with Julie Levison
Featuring Julie Levison, MD, MPH, MPhil

Julie Levison, a physician and researcher at Massachusetts General Hospital, talks about working at Mass General, her early role models, and her advice for women interested in careers in STEM.


Study Highlights the Extent and Impact of Smartphone Use
Featuring Nancy Etcoff, PhD

What impacts do smartphone habits have on our lives beyond the screen? Massachusetts General Hospital psychologist Nancy Etcoff teamed up with Motorola to find out. Their results highlight the pervasiveness of smartphone use and identify a few worrying trends, especially among younger generations, but also suggest we’re not too far gone to regain “phone-life balance”.


Research Awards and Honors: March 2018
Featuring Tayyaba Hasan, PhD, Steven H. Liang, PhD, Ryan Nipp, MD, William Shipley, MD, David Sykes, MD, PhD, and Marc Wein, MD, PhD

Congratulations to the Mass General researchers who received awards and honors this month!